Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied In chronic, diet-induced hypercholesterolemia In a series of nonhuman primates. Within 12 days of hypercholesterolemia In Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipld-laden macrophages (foam cells). Within a month, a "seroflbrinous insudate" formed together with variable numbers of subendothellal llpid-laden macrophages. By the second month, foam cells increased In number, often in multilayers, to form a fatty streak. Concomitantly, the luminal surface of the arteries became increasingly Irregular due to the subendothelial accumulation of foam cells. Numerous monocytes continued to attach to the endothelial surface over the fatty streaks, and many of them appeared to enter the Intlma and participate In the growth of the fatty streaks. Lipid-laden smooth muscle cells appeared in small numbers and formed two to four layers between the macrophages and the internal elastic lamella at 2 to 3 months. During the third month of hypercholesterolemla, endothelial cell continuity over the llpid-laden macrophages became Interrupted, exposing the underlying foam cells to circulating blood. Foam cells were then readily observed In whole blood smears, suggesting that many of the lipld-laden macrophages leave the intima and enter the circulation.After 4 months, significant endothelial denudation was found In the lilac artery and many exposed macrophages were covered by adherent platelets in the form of a mural thrombus. Thus, the early components of atherosclerosis induced by chronic hypercholesterolemla centered around the monocyte-macrophage and its interaction with endothelium In the induction of the fatty streak. Subsequent changes that lead to macrophage-smooth muscle Interactions, platelet-macrophage Interactions, and platelet-endothelial interactions appeared to set the stage for the development of more advanced proliferatlve lesions. (Arteriosclerosis 4:323-340, July/August 1984)

This report presents the second portion of the morphologic studies on chronic, dietinduced hypercholesterolemia in nonhuman primates (Macaca nemestrina) examined sequentially between 5 and 13 months. A direct relationship was observed between the rate of cholesterol increase, the level and duration of hypercholesterolemia, and the changes in the artery wall that led to the formation of fatty streaks and their conversion to fibrous plaques. A loss of endothelial continuity was first observed in the iliac arteries between 3 and 4 months of atherogenic diet and appears to be a critical step in the conversion of many fatty streaks to fibrous plaques. With breaks in endothelial junctions and exposure of some of the macrophages in a fatty streak, many of the lipid-filled macrophages appeared to detach and enter the circulation. The number of circulating foam cells increased precipitously between 3 and 4 months, the time when increased sites of endothelial dysjunction and macrophage egress were observed. Exposure of subendothelial macrophages also permitted adherence of platelets to these macrophages and to exposed connective tissue. Fibrous plaques were found at similar anatomic sites where endothelial denudation had been observed at earlier time points but were more prevalent in the abdominal aorta and iliac arteries. These changes subsequently occurred at every level of the aortic tree and appeared to progress in a cephalad fashion with increasing rate, level, and duration of hypercholesterolemia.The results of these studies stress the importance of following cholesterol levels of each animal throughout the entire period of the study and of sampling the entire arterial tree at every level with time. This helped us to understand the complicated interrelationships between the various cells in atherogenesis, provided further support for the "Response to Injury Hypothesis of Atherosclerosis," and helped to explain how hypercholesterolemia may be involved in the different stages of atherogenesis in nonhuman primates and possibly in humans. (Arteriosclerosis 4:341-356, July/August 1984)

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Abstract-In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer. This review analyzes the current knowledge on the pleiotropic properties of these classes of drugs. Direct comparison indicates that study of the associations among these drugs may eventually disclose additive or synergistic effects that, perhaps even at lower dosages, may provide improved vascular protection and a strong alliance against several atherogenic mechanisms.

Data on the protective role of antioxidants in models of atherosclerosis are only partially confirmed in man. Observational and epidemiological data, as well as randomized trials, provide no clear cut indications, because of positive and disappointing results on the use of antioxidants in cardiovascular protection. Despite the lack of a general consensus, recent data reinforce the concept that the regular intake of antioxidants present in food limits the progression of atherosclerosis. When it is possible to monitor the efficacy of any antioxidant therapy with validated markers of oxidation, the potential influence of vitamins and antioxidants on coronary artery disease may eventually be resolved.